Pseudomonas aeruginosa (PA) is a major public health issue due to its impact on nosocomial infections as well as its impact on cystic fibrosis patient mortality. Pseudomonas aeruginosa (PA) is a Gram-negative, aerobic, glucose non-fermenting bacterium and mobile through polar monotrichous flagellum. It is a clinically important opportunistic pathogen often related to hospital infections, because of its ability to survive for long periods, with minimum nutritional requirements and with high tolerance to environmental variations. PA is responsible for 10-30% of hospital-acquired infections (Floret, N. et al., (2009), Pathol. Biol. 57, 9-12). It is also the most frequent pathogen, progressively leading to chronic inflammation and to the degradation of the respiratory tract of Cystic Fibrosis patients (Lyczak, J. B. et al., (2002) Clinical Microbiology Reviews 15, 194-222). Currently, the use of antibiotics is the only way that can be effective against PA infection. However, in this regard, bacterial multiplication in a biofilm structure seems to give a selective advantage to the pathogen (Stewart, P. S., and Costerton, J. W. (2001) Lancet 358, 135-138. Landry, R. M. et al., (2006) Mol. Microbiol. 59, 142-151).
Consequently, regarding the emergence of resistance of most pathogenic bacteria, especially PA, to antibiotics, the development of new antibacterial agents able to escape the mechanisms of resistance or of new modes of action had become imperative and is a major research challenge to treat or prevent infectious diseases. Therefore, inhibition of PA virulence has been proposed as an alternative strategy to tackle PA based infections.
PA-IL, a galactose binding lectin from PA, is involved in its virulence. Pseudomonas aeruginosa lectin 1 (PA-IL, Lec A) is a tetravalent lectin with nearly a rectangular shape with binding sites distant of 71 Å on the long side, and 32 Å on the short side (Cioci, G. et al., (2003) FEBS Lett. 555, 297-301; Imberty, A., et al., (2004) Microb. Infect. 6, 221-228). The binding of PA-IL for monovalent galactosides span in the micromolar range (with the highest affinity for Phenyl-β-Gal) and is influenced by the structure of the aglycon (Garber, N. et al., (1992) Biochim. Biophys. Acta 1116, 331-333; Chen, C. P. et al., (1998) Glycobiology 8, 7-16).
The binding of PA-IL can reach the nanomolar range when taking advantage of the so-called cluster effect (Lis, H., and Sharon, N. (1998) Chem. Rev. 98, 637-674; Lundquist, J. J., and Toone, E. J. (2002) Chem. Rev. 102, 555-578; Lee, Y. C., and Lee, R. T. (1995) Acc. Chem. Res. 28, 321-327). Multivalent carbohydrate ligands can present enhanced binding to the target lectin per carbohydrate residues as compared to the monovalent ligand. The extent of the enhancement is among others a function of the topology as the residues should fit in the multiple sites of the lectins.
S. Cecioni et al., Chem. Eur. J. 2009, 15, 13232-13240 discloses Calix[4]arene Glycoconjugates targeting PA-IL. However, calixarene conjugates are difficult to prepare, with potential formation of diastereoisomers and potential toxicity of calixarene. F. Pertici et al., Chem. Commun., 2012, 48, 4008-4010 discloses di-galactose derivatives as potent divalent inhibitors of Pseudomonas aeruginosa lectin LecA. The preparation method of these compounds is long and complicated. A. Imberti et al., Chem. Eur. J. 2008, 14, 7490-7499 discloses glycoclusters and their affinity for E. Coli's FimH or Pseudomonas aeruginosea's PA-IIL. I. Deguise et al., New J. Chem., 2007, 31, 1321-1331 discloses the synthesis of glycodendrimers containing both fucoside and galactoside residues and their binding properties to PA-IL and PA-IIL lectins from Pseudomonas aeruginosa. Angew. Chem. Int. Ed. 2011, 50, 10631-10635 discloses a glycopeptide dendrimer inhibitor of biofilms of lectin LecA and of P. aeruginosa. It does not mention the inhibition of PA-IL adhesion.
To compete efficiently with cell surface glycoconjugates, glycomimetics have to present a strong affinity with their target. Low affinity of lectin-carbohydrate interactions is a barrier in the development of biologically active glycomimetic compounds, and multivalency has permitted to overcome partly this difficulty. However, if prior art results confirm the strong potential of glycomimetics for preventing Pseudomonas aeruginosa adhesion, and for use in prevention and treatment of bacterial infection, there remains the need of molecules with a high affinity with PA-IL.
The design and synthesis of such compounds is not easy: the affinity of a glycomimectic for lectin depends not only on the number of carbohydrate groups displayed by the molecule and capable of interacting with lectin PA-IL. It also depends on their arrangement in the molecule: the nature, length and flexibility of linker arms binding the carbohydrate groups to the rest of the molecule. Moreover, on account of complicated synthesis, many prior art glycomimetics are accessible in small quantities only.
There remains the need for molecules presenting a strong affinity for pathogen lectins, notably for PA-IL. Notably, there remains the need for molecules capable of inhibiting the adhesion of P. aeruginosa, thereby inhibiting the formation of a biofilm of P. aeruginosa. Such molecules should be capable of being produced by simple and efficient methods to give access to a medicament.